Sex and Menstrual Cycle Effects on Progressive Ratio Measures of Cocaine Self-Administration in Cynomolgus Monkeys

Abstract

Fluctuations in ovarian steroid hormones across the menstrual/estrous cycle influence the abuse-related effects of acute cocaine administration in women and chronic cocaine self-administration in rodents, but there have been no comparable studies in non-human primates. The interactions among sex, menstrual cycle phase, and cocaine self-administration (0.0032, 0.01, and 0.032 mg/kg/injection (inj)) under a progressive ratio schedule were investigated in four female and two male cynomolgus monkeys. Females were given unrestricted access to cocaine across 54 menstrual cycles, and males were studied over 23 pseudo-cycles of 30 days duration. Ovulatory cycles were defined by luteal phase elevations in progesterone and 44 cycles were ovulatory. During ovulatory menstrual cycles, females reached significantly higher progressive ratio break points than males at all three unit doses of cocaine (Po0.001). During anovulatory cycles, females also reached significantly higher break points than males for 0.032 mg/kg/inj cocaine (Po0.01). Progressive ratio break points for cocaine (0.01 and 0.032 mg/kg/inj) did not vary significantly as a function of ovarian steroid hormone levels during the follicular and the luteal phase of ovulatory menstrual cycles, or during anovulatory cycles. Progressive ratio break points for 0.0032 mg/kg/inj cocaine were significantly higher during the follicular phase than during the late luteal phase (Po0.05-0.001). There were no systematic changes in progressive ratio break points in male pseudo-cycles. Significant cocaine dose-related sex differences were observed, but no consistent changes in cocaine self-administration as a function of menstrual cycle phase, or levels of estradiol and progesterone, were detected in female cynomolgus monkeys.

Effects of Estradiol on Cocaine Self-Administration and Cocaine Discrimination by Female Rhesus Monkeys

“…Normally cycling cynomolgus females also did not alter patterns of cocaine self-administration as a function of menstrual cycle phase at unit doses on the ascending limb of the cocaine dose-effect curve (Mello et al, 2007). Findings in the present study are consistent with clinical studies in which estradiol failed to enhance responses to d-amphetamine (Justice and de Wit, 2000a, b).…”

“…Similarly, cynomolgus female monkeys did not alter patterns of cocaine self-administration as a function of menstrual cycle phase when reinforcing unit doses of cocaine were available (0.01 and 0.032 mg/kg/inj.) (Mello et al, 2007). Progressive ratio breakpoints were stable across 34 menstrual cycles in which ovulation was verified by a mid-luteal phase elevation of progesterone (Mello et al, 2007).…”

“…(Mello et al, 2007). Progressive ratio breakpoints were stable across 34 menstrual cycles in which ovulation was verified by a mid-luteal phase elevation of progesterone (Mello et al, 2007). However, when a low dose of cocaine (0.0032 mg/kg/ inj.)…”

“…However, when a low dose of cocaine (0.0032 mg/kg/ inj.) was available that did not maintain reliable or robust cocaine self-administration, progressive ratio breakpoints were significantly higher during the early-and midfollicular phase than during the late luteal phase of 10 ovulatory menstrual cycles (Mello et al, 2007).…”

“…In endocrine studies in rhesus monkeys, cocaine stimulated estradiol release only during the follicular phase when estradiol was unopposed by progesterone, and not during the luteal phase when progesterone levels were high (Mello et al, 2000). We examined cocaine self-administration during ovulatory menstrual cycles in cynomolgus female monkeys (Mello et al, 2007). There were no consistent changes in progressive ratio break points for reinforcing unit doses of cocaine (0.01 and 0.032 mg/kg/inj.)…”